Real-World Data on the Use of Intravenous Fosfomycin for the Treatment of Central Nervous System Infections: a Subgroup Analysis from the FORTRESS Study

INTRODUCTION: Central nervous system (CNS) infections are associated with high morbidity and mortality, and their management is challenged by antimicrobial resistance and limited cerebrospinal fluid (CSF) penetration of many antibiotics. Intravenous fosfomycin (FOS) offers broad-spectrum activity, favourable pharmacokinetics and reliable CSF penetration, making it a potential partner in combination therapy for severe CNS infections. This interim subgroup analysis of the prospective FORTRESS study evaluated real-world treatment patterns, effectiveness and safety of FOS in patients with CNS infections. METHODS: FORTRESS is an ongoing multicentre, non-interventional, international study enrolling patients receiving FOS for severe infections. We analysed patients with documented CNS infections among 1019 enrolled up to June 2025. Effectiveness endpoints at end of treatment (EOT) included clinical success (composite endpoint defined as successful clinical response plus concomitant microbiological cure), successful clinical response (defined as complete or partial resolution of signs and symptoms), microbiological cure, clinical failure and in-hospital mortality. Safety outcomes included adverse drug reactions (ADRs; including serious ADRs) and laboratory parameters. RESULTS: A total of 64 patients with CNS infections were included, of which most were critically ill at baseline, with high rates of ICU admission (90.6%), sepsis (42.2%) and mechanical ventilation (35.9%). Included patients were treated for ventriculitis (53.1%), brain abscess/empyema (26.6%), bacterial meningitis (26.6%) and shunt infections (18.8%), mainly caused by Staphylococcus spp. (48.8%). FOS was administered exclusively in combination regimens, generally as second- or third-line therapy, at high daily doses (median 22.1 g/day). At EOT, clinical success was achieved in 82.8% of patients, a successful clinical response in 92.2% and microbiological cure in 85.9%. All-cause in-hospital mortality was 12.5%. Outcomes were especially favourable in bacterial meningitis (94.1% clinical success) and Gram-positive infections (96.6% clinical success). FOS was generally well tolerated. Electrolyte imbalances were the most common ADRs but were mainly mild and did not require treatment modification. CONCLUSIONS: These interim real-world data suggest that FOS, used in combination with other antimicrobial agents, is an effective and well-tolerated treatment option for severely ill patients with CNS infections. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT02979951.